Project Summary/Abstract Candidate: My ultimate career goal is to become a successful, independent clinician scientist making important discoveries in the field of neurodegeneration and then translating those findings into therapies for patients in the clinic. In addition, I would like to remain intimately involved in training our future clinicians and scientists. Overall, I understand the necessity of a translational approach to develop therapies and improve the lives of our patients. The Mentored Clinical Scientist Career Development Award will complete the necessary training for my transition to independence as I establish my own research group to study novel mechanisms of disease pathogenesis. Training: Dr. James Lah will serve as my primary mentor with Dr. Allan Levey as co-mentor. I have been fortunate to learn from them over the last few years and am confident that the plan we have developed will provide the necessary career training to conduct the research proposed and assist in my transition to independence. We have put together a group of faculty members, including Dr. Peng Jin, Dr. Nicholas Seyfried and Dr. Ann McKee who will also provide training through technical guidance and intellectual support. Dr. Peng Jin will provide expertise in designing, executing and analyzing data from the small nuclear RNA (snRNA) aggregation and RNA sequencing experiments while Dr. Nicholas Seyfried will advise on design and analysis of the phosphoproteomic experiments. Dr. McKee will provide training in the pathologic diagnosis of chronic traumatic encephalopathy and assist with planning experiments with CTE tissues. To augment training from my contributors, I will attend the Computational and Comparative Genomics Course at Cold Springs Harbor Laboratory. I will also attend the University of Pittsburgh Course in Scientific Management and Leadership and Emory Junior Faculty Development Course, which will help develop my leadership skills to increase personal and team productivity once my own research group is established. I will plan to present findings at the International Conference on Alzheimer's Disease and annual meetings for the American Neurological Association and American Academy of Neurology. I will continue to attend weekly seminars in the Emory Center for Neurodegenerative Disease, weekly lab meetings, and relevant biochemistry and genetics seminars to ensure broad exposure to neurodegenerative diseases and available techniques for scientific study. Research: A common thread in neurodegeneration is the pathologic accumulation of microtubule associated protein tau (MAPT). Significant advances have led to a better understanding of tau intracellular physiology, however therapies have remained elusive due to the lack of critical insights concerning why tau and other proteins aggregate and how these aggregates disrupt cellular homeostasis. We recently demonstrated striking enrichment of multiple small nuclear ribonucleoproteins (snRNPs) with tau in AD, the most common tauopathy. snRNPs comprise the RNA spliceosome and are required for converting precursor-mRNA (pre-mRNA) into mRNA for use in protein translation. In addition to biochemical enrichment, immunohistochemistry studies displayed cytoplasmic tangle-like aggregations of snRNP components, including uridine-rich small nuclear RNA (snRNA), aberrantly localized with tau-positive neurofibrillary tangles in AD. Moreover, these changes were associated with widespread perturbations in RNA processing, suggesting a loss of snRNP/spliceosome function in AD. Remarkably, these snRNP alterations were specific to AD, with no changes detected in other neurodegenerative diseases like Parkinsons, ALS, or other tauopathies, such as FTD-tau, CBD, and PSP. Interestingly, our recent pilot data demonstrate snRNP alterations in CTE that are similar to those seen in AD. Just how these snRNP aggregates cause disease, however, remains unclear. We hypothesize that they contribute to AD and CTE pathogenesis by promoting tau aggregation, altering tau splicing, and disrupting the splicing of other key mediators that interact with tau. To test this postulate, we will first determine if snRNA, which is also found in the cytoplasmic tangle-like aggregates, can directly promote tau aggregation. We will also determine if MAPT alternative splicing is affected by the aggregation of RNA splicing factors, such as SC35. Finally, changes in RNA processing in AD brains suggest functional consequences of disrupted RNA splicing machinery demonstrated by our pathological and biochemical studies; therefore, we will perform more detailed RNA sequencing to identify disease-relevant RNA splicing changes in AD and CTE. These hypotheses and experiments will provide crucial insights into mechanisms of disease for AD and other tauopathies. Results will elucidate new targets and pathways that will be useful in developing therapies for these untreatable illnesses. Finally, the data and skills that I acquire will provide a foundation for my independent research career as a translational clinician scientist.